Highly mineralized osteogenic sponge compositions and uses thereof

ABSTRACT

Osteogenic sponge compositions having enhanced osteoinductive properties for use in bone repair are described. The compositions include a quickly resorbable porous carrier, a more slowly resorbed mineral scaffold and an osteogenic factor, preferably a bone morphogenetic protein. The compositions enable increased osteoinductive activity while retaining a reliable scaffold for the formation of new bone at an implant site. Methods for therapeutic use of the compositions are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/923,116, filed Aug. 6, 2001, now U.S. Pat. No. 7,563,455, the entirecontents of which is hereby incorporated by reference. U.S. patentapplication Ser. No. 09/923,116 is a continuation of 35 U.S.C. §371 ofInternational Application No. PCT/US00/03043, filed on Feb. 4, 2000,which claims priority from U.S. Patent Application No. 60/118,615 filedon Feb. 4, 1999, both of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to osteogenic compositions.Specifically, the present invention relates to an osteogenic spongecomposition effective for the induction of new bone growth in animals.

BACKGROUND OF THE INVENTION

Bone grafting has been commonly used to augment healing in the treatmentof a broad range of musculoskeletal disorders. This procedure hasseveral disadvantages. If the bone material is obtained from donors ofthe same species, such as an allograft, an increased risk of diseasetransmission and immune reaction exists. Bone material surgicallyremoved from the patient, known as an autograft, is also undesirablebecause a sufficient amount of autogenous bone may not be available andthe additional surgery necessary to obtain the autograft increases therisk of infection.

Due to the need for safer bone graft materials, efforts have beendirected to finding bone graft substitutes. Candidate compositionsinclude collagen and a bioceramic, such as hydroxyapatite, as thesecomponents are the chief structural materials in bone tissue.Bioceramics provide a porous matrix which encourages some new bonegrowth but, when used in powdered form, give rise to foreign body-giantcell reactions. Other compositions include demineralized bone powder andcollagen. The osteogenic potential of these compositions have been foundto be less than satisfactory.

The discovery of osteogenic factors and their application to bone graftsubstitute compositions has increased the effectiveness of theabove-mentioned compositions. Although many preparations purport to beeffective in bone repair in vertebrates, including higher animals suchas primates, most of the experimentation done with the compositions haveinvolved lower animals, such as mice and rats.

In light of this background, there remains a need for improvedosteogenic compositions and methods that effectively induce bone growthin higher animals, including primates.

SUMMARY OF THE INVENTION

The invention provides in one preferred embodiment an osteogenic spongecomposition useful for the induction of new bone growth in a mammal.This composition includes a resorbable sponge matrix material and anosteogenic factor, preferably one that preferably stimulates osteoblastsand osteoclasts, said osteogenic factor incorporated in the spongematrix material. The resorbable sponge matrix material is desirably athree-dimensionally stable yet flexible material, facilitating its useas an implant. The osteogenic factor is usually incorporated in anamount that causes an increased rate of resorption of said sponge matrixmaterial in a mammal. The composition also includes a particulatemineral having an average particle diameter of at least about 0.5 mmembedded in the resorbable sponge matrix material, wherein theparticulate mineral present in a weight ratio of at least 4:1 relativeto the resorbable sponge matrix material so as to provide a scaffold forbone ingrowth in the presence of the osteogenic factor. More preferredcompositions are even more highly mineralized, for example wherein theparticulate mineral is present in a weight ratio of at least about 10:1relative to the resorbable sponge matrix material. The particulatemineral is desirably formed of a synthetic calcium phosphate ceramic orof bone, especially cortical bone. The osteogenic factor is mostpreferably BMP-2 or LMP, or comprises a nucleotide sequence encodingBMP-2 or LMP.

Another embodiment of the present invention provides a method forinducing bone growth in a primate. The method includes a first step ofproviding an osteogenic sponge composition having a resorbable spongematrix material and an osteogenic factor that stimulates osteoblasts andosteoclasts incorporated in the sponge matrix material in an amount thatcauses an increased rate of resorption of the sponge matrix material inthe primate. Particulate mineral having an average particle diameter ofat least about 0.5 mm is embedded in said resorbable sponge matrixmaterial and present in a weight ratio of at least 4:1 relative to theresorbable sponge matrix material, so as to provide a scaffold for boneingrowth in the presence of the osteogenic factor. This osteogenicsponge composition is implanted in the primate in a void in which bonegrowth is desired, with the osteogenic sponge composition providing ascaffold for a duration sufficient for osteoid ingrowth through thevoid. Particularly preferred methods involve bone ingrowth to attainspinal fusions in humans.

Another preferred embodiment of the invention provides an osteogenicsponge composition effective for the induction of new bone growth in amammal (especially a primate) that includes

a carrier consisting essentially of a resorbable sponge matrix withparticulate mineral embedded in the resorbable sponge matrix, whereinthe particulate mineral is present in an amount constituting at leastabout 95% by weight of the carrier. An osteogenic factor that stimulatesosteoblasts and osteoclasts is incorporated in said carrier.

A still further aspect of the invention provides a highly mineralizedsponge implant device consisting essentially of a resorbable spongematrix formed of collagen and having particulate biocompatible mineralembedded within said matrix. In this embodiment, the device is comprised1% to 3% by weight of the collagen and 97% to 99% by weight of theparticulate biocompatible mineral. In another inventive feature, anosteogenic factor can be incorporated in such an implant.

A further embodiment of the invention provides an interbody spinalfusion device that includes a load bearing member sized for insertionbetween adjacent vertebrae and any one of the aforementionedcompositions retained by the load bearing member. Such fusion devicescan be used in inventive interbody spinal fusion methods mammals,wherein the devices are appropriately implanted to facilitate spinalfusion.

A particular feature of the present invention relates to the discoverythat the inclusion of an osteogenic factor, especially an osteoblast-and osteoclast-stimulating osteogenic factor, in a resorbable spongecomposition causes a substantially accelerated resorption of the sponge.This rapid resorption can diminish or eliminate the capacity of thesponge composition to effectively stimulate and support new boneformation in a void filled with the sponge composition. This isparticularly the case in primates, including humans, in which the rateof new bone formation is relatively slow. Objects of the presentinvention are to provide osteogenic sponge compositions effective forthe induction of bone growth in mammals, particularly primates,including humans, and related methods and devices. These and otherobjects and advantages of the present invention will become apparentupon reading the descriptions herein.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 and 2 depict a digitized images of computerized tomography (CT)scans of an L4-L5 posterolateral spinal fusions performed on rhesusmonkeys as described in Example 5 (top panels, section through superiortransverse processes; middle panels, section through disc space; lowerpanels, section through inferior transverse processes).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to preferred embodiments andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations and furthermodifications of the invention, and such further applications of theprinciples of the invention as illustrated herein, being contemplated aswould normally occur to one skilled in the art to which the inventionrelates.

As described above, the invention relates in certain aspects toosteogenic sponge compositions effective for the induction of new bonegrowth in mammals and methods for inducing bone growth in mammals. Thepresent invention features osteogenic sponge compositions effective foruse in primates, wherein the compositions exhibit high osteoinductivepotential and provide a lasting mineral scaffold to support boneingrowth. Such preferred compositions include a porous, resorbablesponge carrier, such as collagen in sponge form, and an osteogenicfactor that stimulates the action of both osteoblasts (whichbiologically facilitate the formation of bone) and osteoclasts (whichbiologically facilitate the resorption of bone). In accordance with thepresent invention, it has been found that the incorporation of aneffective inductive amount of an osteogenic factor, such as a bonemorphogenetic protein (BMP), stimulates osteoclasts to such a level thata porous resorbable carrier is quickly resorbed and, in the absence of ahigh mineral component in the composition, causes the performance of thecomposition to suffer in some cases to the extent that the observationof substantial bone ingrowth is sporadic. Although such non-mineralizedsponge compositions may be highly effective for repair of bone defectsin lower animals, such as mice, that have a faster bone growth rate,they are less effective in large animals such as primates, includinghumans.

Accordingly, a feature of the present invention is the provision of anosteogenic composition in the form of a sponge that includes asubstantial amount of a relatively slowly-resorbed mineral componentthat remains at the implant site after the carrier has been rapidlyresorbed, in order to provide a scaffold for new bone formation that isnot prematurely resorbed due to the osteoclastic potentiation by thebone morphogenic protein in the composition. The present invention alsoprovides methods for using such osteogenic compositions in treatment ofbone trauma, disease and defects, for artificial arthrodeses and forother treatment where new bone formation is desired, especially inprimates, including humans.

The sponge matrix material is preferably collagenous. A wide variety ofcollagen materials are suitable for the sponge matrix. Naturallyoccurring collagens may be subclassified into several different typesdepending on their amino acid sequence, carbohydrate content andpresence or absence of disulfide cross-links. Types I and III collagenare two of the most common subtypes of collagen. Type I collagen ispresent in skin, tendon and bone whereas Type III collagen is foundprimarily in skin. The collagen in the composition may be obtained fromskin, bone, tendon, or cartilage and purified by methods known in theart. Alternatively, the collagen may be purchased commercially. Thecollagen in the composition is preferably Type I bovine collagen.

The collagen carrier can further be atelopeptide collagen and/ortelopeptide collagen. Moreover, both non-fibrillar and fibrillarcollagen may be used. Non-fibrillar collagen is collagen that has beensolubilized and has not been reconstituted into its native fibrillarform.

The sponge carrier may also be formed of other natural or syntheticpolymeric materials, in addition to or as an alternative to collagen.For example, the sponge carrier may be formed of gelatin (e.g. foamedgelatin), in addition collagen or as an alternative to collagen. Othernatural and synthetic polymers are also known for the formation ofbiocompatible sponge materials, and can be used herein.

As indicated above, preferred compositions of the invention also includean osteoinductive factor, such as an osteoinductive protein or anucleotide sequence encoding an osteoinductive protein operablyassociated with a promoter (e.g. provided in a vector such as a viralvector) which drives expression of the gene in the animal recipient toproduce an effective amount of the protein. The osteogenic factorutilized in the present invention can be one that stimulates productionor activity of osteoblasts and osteoclasts. The factor is preferably abone morphogenetic protein (BMP) or a LIM mineralization protein (LMP),or comprises a nucleotide sequence encoding a BMP or LMP. Recombinanthuman BMPs are preferred, and may be commercially obtained or preparedas described and known in the art, e.g. in U.S. Pat. No. 5,187,076 toWozney et al.; U.S. Pat. No. 5,366,875 to Wozney et al.; U.S. Pat. No.4,877,864 to Wang et al.; U.S. Pat. No. 5,108,932 to Wang et al.; U.S.Pat. No. 5,116,738 to Wang et al.; U.S. Pat. No. 5,013,649 to Wang etal.; U.S. Pat. No. 5,106,748 to Wozney et al; and PCT Patent Nos.WO93/00432 to Wozney et al.; WO94/2693 to Celeste et al.; and WO94/26892to Celeste et al. Further, the osteoinductive factor may be isolatedfrom bone. Methods for isolating BMP from bone are described in U.S.Pat. No. 4,294,753 to Urist and Urist et al., PNAS 371, 1984.Recombinant human BMP-2 (rhBMP-2), recombinant human BMP-4 (rhBMP-4),recombinant human BMP-7 (rhBMP-7) or heterodimers thereof are mostpreferred. The osteoinductive factor may also be LIM mineralizationprotein (LMP) or a suitable vector incorporating a gene encoding thesame operably associated with a promotor, as described in WO99/06563(see also genbank accession No. AF095585). When such vectors areemployed as osteogenic factors in accordance with the invention, theyare preferably delivered in conjunction with cells, for exampleautologous cells from the recipient of the implant. Most preferably thevector is delivered in conjunction with autologous white blood cellsderived from bone marrow or peripheral blood of the recipient. Thesecells may be applied to the sponge composition along with the osteogenicfactor prior to implantation.

The particulate mineral component includes a natural or syntheticmineral that is effective in providing a scaffold for bone ingrowth asthe resorbable carrier is resorbed. The mineral may be, for example,bone, especially cortical bone, or a synthetic bioceramic such as abiocompatible calcium phosphate ceramic. Illustrative ceramics includetricalcium phosphate, hydroxyapatite, and biphasic calcium phosphate.These mineral components may be purchased commercially or obtained orsynthesized by methods known in the art.

Biphasic calcium phosphate is a particularly preferred synthetic ceramicfor use in the invention. Desirably, such biphasic calcium phosphatewith have a tricalcium phosphate:hydroxyapatite weight ratio of about50:50 to about 95:5, more preferably about 70:30 to about 95:5, evenmore preferably about 80:20 to about 90:10, and most preferably about85:15.

In general, the amount of mineral in the osteogenic sponge compositionmust be sufficient to provide a scaffold that will remain in the patientfor a period of time sufficient for the formation of osteoid in the voidfor which bone growth is desired. Typically, this period of time will beabout 6 to about 8 weeks. The minimum level of mineral that must bepresent in the composition is also dependent on the activity of the BMPin the composition; the higher the activity of the BMP, the greater thecontent of the mineral matrix required to counter the osteoclasticpotentiation of the BMP. The rate of resorption of the resorbablecarrier also increases as the BMP concentration increases.

In preferred aspects of the invention, the particulatemineral:resorbable sponge matrix weight ratio will be at least about4:1, more preferably at least about 10:1. In particularly preferredsponge implants, the particulate mineral will constitute at least 95% byweight of the sponge implant. For example, highly effective spongecarrier devices are provided wherein they comprise about 97% to about99% by weight particulate mineral and about 1% to about 3% of thecollagen or other sponge-forming matrix material. Moreover, it ispreferred that the mineral component have an average particle size of atleast about 0.5 mm, more preferably about 0.5 mm to about 5 mm, and mostpreferably about 1 mm to about 3 mm.

To make the sponge implant, a collagen slurry may be formed as known andpreferably is chilled to increase its viscosity to help suspend theporous particulate mineral component. The porous particulate mineral isdispersed into the collagen slurry and gently mixed. After the porousparticulate mineral component is uniformly dispersed in the slurry, theslurry is poured into sterile trays or other forms and freeze dried. Thesheets of composite sponge are then removed from the freeze drier andexposed to a gluteraldehyde cross-linking agent. The composite spongeformed is generally three-dimensionally stable and can be sterilized andpackaged in accordance with known procedures.

The dimensions of the sponge produced may vary depending on theapplication. Dimensions of a typical sponge are, for example, about 10cm (length)×7.5 cm (width)×0.35 cm (height).

As one example, BMP or other osteogenic factors may be included in theformed sponge by combining the BMP with a liquid carrier as known in theart and infusing the liquid into the sponge.

As further enhancements of the compositions of the present invention,those skilled in the art will readily appreciate that other osteogenicenhancing factors may be incorporated into the composition. Suchadditional factors include host compatible osteogenic progenitor cells,autographic bone marrow, allographic bone marrow, transforming growthfactor-β, fibroblast growth factor, platelet-derived growth factor,insulin-like growth factor, microglobulin-β, antibiotics and steroids.

In yet another aspect of the invention, methods for inducing bone growthin mammals are provided. The methods include providing theabove-described osteogenic sponge composition and implanting thecomposition at a site at which bone growth is desired, e.g., to treat adisease, defect or location of trauma, and/or to promote artificialarthrodesis. The hydrated sponge composition may be rolled up prior topacking the sponge into the implantation site.

Once in place, the osteogenic sponge composition will effectively induceand support ingrowth of bone into the desired area even in a primatesuch as a human that exhibits a relatively slow rate of bone formationcompared to smaller mammals, such as rodents or rabbits. Although thecollagen carrier is resorbed relatively quickly, the substantial mineralcomponent remains as a scaffolding to support new bone growth in andthrough the desired area.

The above osteogenic sponge compositions of the present invention areespecially advantageous when used in bones or bone portions that exhibitonly low to moderate vascularization. Such low to moderate vascularizedregions exhibit low rates of bone formation so rapid resorption of acarrier poses a problem. Examples of low to moderate vascularized sitesinclude, for example, transverse processes or other posterior elementsof the spine.

An especially preferred use of the sponge compositions of the presentinvention is as an implant to promote arthrodesis between vertebrae inspinal fusions in humans or other primates, including interbody,posterior and/or posterolateral fusion techniques. Although the rate ofbone formation in the primate spine is relatively slow overall and thuswill benefit generally from the present invention, the elements to befused in posterior and posterolateral fusions exhibit particularly lowlevels of vascularization and thus fusions of these elements areexpected to benefit markedly from the invention.

Moreover, the osteogenic sponge compositions can be incorporated with aload-bearing member used in a spinal fusion, including hollow spinalcages, dowels or other devices known in the art having a pocket, chamberor other mechanism for retaining the osteogenic sponge composition. Theload-bearing member desirably will have a compressive strength of atleast about 10,000 N. Suitable such load bearing members are described,for example in U.S. Pat. Nos. 5,522,899, 5,785,710, 5,776,199 and5,814,084, each of which is hereby incorporated by reference in itsentirety.

Reference will now be made to specific examples using the processesdescribed above. It is to be understood that the examples areillustrative and not limiting of the invention.

EXAMPLE 1 Preparation of Collagen Sponge/Bone Particle Composite

12 grams of deproteinized cortical bone chips, 1-3 mm in size, wereadded to 12 grams of collagen slurry (0.192 grams of collagen). Thiscomposite slurry was poured into a 7.5 cm×10.0 is cm mold, freeze dried,double sterile packaged, and sterilized by ETO gas sterilization.

EXAMPLE 2 Preparation of Collagen Sponge/Synthetic Ceramic Composite

12 grams of biphasic calcium phosphate particles, 1 mm in diameter, wereadded to 12 grams of collagen slurry (0.192 grams of collagen). Thiscomposite slurry was poured into a 7.5 cm×10.0 cm mold, freeze dried,double sterile packaged, and sterilized by ETO gas sterilization.

EXAMPLE 3 Preparation of Collagen Sponge/Bone Particle Composite

12 grams of deproteinized cortical bone chips, 1-3 mm in size, wereadded to 24 grams of collagen slurry (0.192 grams of collagen). Thiscomposite slurry was poured into a 7.5 cm×10.0 cm mold, freeze dried,double sterile packaged, and sterilized by ETO gas sterilization.

EXAMPLE 4 Preparation of Collagen Sponge/Synthetic Ceramic Composite

12 grams of biphasic calcium phosphate particles, 1 mm in diameter, wereadded to 24 grams of collagen slurry (0.192 grams of collagen). Thiscomposite slurry was poured into a 7.5 cm×10.0 cm mold, freeze dried,double sterile packaged, and sterilized by ETO gas sterilization.

EXAMPLE 5 L4-L5 Posterolateral Intertransverse Process Spinal FusionStudy

The present study was performed to determine the effect of theosteogenic sponge compositions of the present invention on spinalfusion.

The experimental group included two adult rhesus monkeys (Macacamulatta). The monkeys were anesthetized with 3-5 mg/kg telazolintramuscularly (i.m.). The anesthesia was maintained with 1.5-2.0%isoflurane. After anesthesia was achieved, animals were shaved, preparedwith betadine and sterily draped. The surgical site was infiltrated with10-15 ml of 0.25% marcaine to aid with immediate postoperativeanalgesia. A midlineposterior skin incision was made over the lumbarspine. The paraspinal muscles were reflected using elevators, exposingthe lamina and the transverse processes of the L4 and L5 vertebralbodies. The transverse processes of the two vertebrae to be fused weredecorticated with an electric burr.

Composite sponges, having dimension of 3.5 cm×1.4 cm×0.35 cm, wereprepared using techniques as described in Examples 1 and 2. The spongesincluded, on a weight basis, 97% biphasic calcium phosphate (15%hydroxyapatite and 85% tricalcium phosphate, 1 mm particle size) and 3%collagen. Recombinant human BMP-2 (rhBMP-2) was prepared at aconcentration of 3.0 mg/ml in a buffered solution. Each sponge wasinfused with 1.5 ml of the rhBMP-2 solution.

The sponges were placed in the paraspinal bed directly on top of andbridging the two adjacent transverse processes. The sponges were placedbilaterally, with two sponges (one on top of the other) on each side ofthe spine, resulting in a total dose of 9 mg rhBMP-2 per implant site.The animals were allowed to recover and move around ad libitum withoutrestrictions during the study period.

The spines were manually assessed for fusion upon sacrifice (2, 4 and 6months) and determined to be fused based upon the absence of motionduring attempted bending, and presence of histological bridging bone.

The fusions were also evaluated by CT scan at 2, 4 and 6 months afterimplantation. FIGS. 1 and 2 show the CT scans for each subject studied.FIGS. 1 and 2 demonstrate the sequence of events that occur within thecomposite sponge carrier loaded with rhBMP-2. On the far left of thefigures are three CT sections equally spaced throughout the fusion massat 2 months post-operative, showing that resorption of the compositesponge is just about complete due to the lack of radiopacity of theceramic granules. The three middle CT sections show these same three CTsections at four months with increased bone deposition where the carrieronce resided. The composite sponge has maintained the space within thesoft tissue site for a sufficient enough period of time for the desiredvolume of new bone deposition to occur. Finally, the far right three CTscans show even further bone deposition, remodeling and maturation withthe formation of outer cortices around the periphery of the fusionmasses by six months.

What is claimed is:
 1. An osteogenic sponge composition useful for theinduction of new bone growth in a mammal, comprising: a resorbablesponge matrix material comprising collagen and a particulatebiocompatible mineral comprising a ceramic material embedded within saidresorbable sponge matrix material, the resorbable sponge matrix materialbeing three-dimensionally stable but flexible and comprising 95% to 99%by weight of the particulate biocompatible mineral; and an osteogenicfactor, comprising a bone morphogenic protein, said osteogenic factorincorporated in said sponge matrix material in an amount that causesresorption of said sponge matrix material in a mammal, wherein theresorbable sponge matrix material provides a scaffold for bone ingrowthin the presence of said osteogenic factor.
 2. The osteogenic spongecomposition of claim 1, wherein said resorbable sponge matrix comprises1% to 3% by weight of collagen and 97% to 99% by weight of theparticulate biocompatible mineral.
 3. The osteogenic sponge compositionof claim 2, wherein said osteogenic sponge composition exhibitssufficient flexibility to be rolled up when hydrated.
 4. The osteogenicsponge composition of claim 3, wherein said particulate biocompatiblemineral is resorbed more slowly than the collagen when said osteogenicsponge composition is implanted in said mammal.
 5. The osteogenic spongecomposition of claim 1, wherein said particulate biocompatible mineralis selected from the group consisting of bone particles andbiocompatible synthetic calcium phosphate ceramics.
 6. The osteogenicsponge composition of claim 5, wherein said particulate biocompatiblemineral comprises biphasic calcium phosphate.
 7. The osteogenic spongecomposition of claim 6, wherein said biphasic calcium phosphate has aporosity of at least about 50%.
 8. The osteogenic sponge composition ofclaim 7, wherein said particulate biocompatible mineral includes boneparticles.
 9. The osteogenic sponge composition of claim 8, wherein saidbone particles are cortical bone particles.
 10. The osteogenic spongecomposition of claim 1, wherein said particulate biocompatible mineralcomprises 15% by weight hydroxyapatite and 85% by weight tricalciumphosphate based on the total weight of said particulate biocompatiblemineral embedded within said resorbable sponge matrix material and saidresorbable sponge matrix material comprises 3% by weight collagen. 11.The osteogenic sponge composition of claim 1, wherein said particulatebiocompatible mineral has an average particle size in the range of about0.5 mm to about 5.0 mm.
 12. The osteogenic sponge composition of claim1, wherein said particulate biocompatible mineral has an averageparticle size in the range of about 1 mm to about 2 mm.
 13. Theosteogenic sponge composition of claim 1, wherein said particulatebiocompatible mineral comprises biphasic calcium phosphate havingtricalcium phosphate to hydroxyapatite weight of about 50:50 to about95.5.
 14. The osteogenic sponge composition of claim 1, wherein saidbone morphogenetic protein is a recombinant human protein.
 15. Theosteogenic sponge composition of claim 14, wherein said bonemorphogenetic protein is BMP-2 or BMP-7.
 16. The osteogenic spongecomposition of claim 15, further comprising an osteogenic enhancingfactor selected from the group consisting of autographic bone marrow,allographic bone marrow, transforming growth factor β, fibroblast growthfactor, platelet-derived growth factor, insulin-like growth factor,microglobulin β, and steroids.
 17. An osteogenic sponge compositioncomprising: a highly mineralized sponge implant device, said devicecomprising a resorbable sponge matrix material formed of lyophilizedcollagen and having a particulate biocompatible mineral comprising aceramic material embedded within said resorbable sponge matrix material,the resorbable sponge matrix material being three-dimensionally stablebut flexible and comprising 95% to 99% by weight of the particulatebiocompatible mineral; an osteogenic factor comprising bone morphogenicprotein-2 that stimulates osteoblasts and osteoclasts, said osteogenicfactor incorporated in said device in an amount that causes an increasedrate of resorption of said sponge matrix material in a primate; whereinsaid particulate biocompatible mineral is resorbed more slowly than saidresorbable sponge matrix material, so as to provide a scaffold for boneingrowth that remains in the primate after said resorbable sponge matrixis resorbed.
 18. The sponge composition of claim 17 wherein the primateis a human.
 19. A method for inducing bone growth in a primate,comprising: (a) providing an osteogenic sponge composition comprising: aresorbable sponge matrix material comprising collagen and a particulatebiocompatible mineral comprising a ceramic material embedded within saidmatrix material, the resorbable sponge matrix material beingthree-dimensionally stable but flexible and comprising 95% to 99% byweight of the particulate biocompatible mineral; an osteogenic factorcomprising a bone morphogenic protein that stimulates osteoblasts andosteoclasts, said osteogenic factor incorporated in said sponge matrixmaterial in an amount that causes resorption of said sponge matrixmaterial in the primate; wherein the resorbable sponge matrix materialprovides a scaffold for bone ingrowth in the presence of said osteogenicfactor; and (b) implanting said osteogenic sponge composition in an areain which bone growth is desired in the primate, said osteogenic spongecomposition providing a scaffold for a duration sufficient for osteoidingrowth through an area in which said osteogenic sponge composition isimplanted.